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Genetic counseling: Friedreich Ataxia
Friedreich Ataxia Contracting *Acknowledge prior contact *What do they know about Friedreich Ataxia? *Do they have any questions? Etiology *Slowly progressive ataxia with onset usually during adolescence *Autosomal recessive inheritance *Majority of cases caused by mutations in X25/FRDA gene **Found on chromosome 9q13 **<1% of patients who meet the clinical diagnostic criteria do not have an identifiable mutation in this gene **96% of patients with FRDA1 are homozygous for a GAA expansion in the X25 gene ***Normal alleles have 7-38 repeats ***Premutation alleles have 34-60 repeats ***Disease-causing alleles 66-1700 triplets ***GAA repeat length is unstable during germ line transmission: ****Maternal transmission gives both contractions and expansions ****Paternal transmission usually contracts repeat size but premutation alleles may expand in size ***Larger expansion size correlates with earlier onset of disease *X25 gene codes for a protein called frataxin **Found in inner mitochondrial membrane **Putative iron transporter to regulate mitochondrial iron content Incidence and Carrier Frequency *Population frequency of 2-4 per 100,000 *Carrier frequency is 1/60-1/100 Clinical Features *Obligatory diagnostic criteria: **Progressive ataxia of gait and limbs **Absent reflexes in legs **Dysarthria **Decrease in position sense and/or vibration in lower limbs **Muscle weakness **Motor nerve conduction velocity of >40 m/s with reduced or absent sensory nerve action potential *Additional findings: **Scoliosis **Pes cavus **Cardiomyopathy (66%) ***Usually in later stages of disease but may precede ataxia ***2/3 of patients have abnormal EKG **Optic nerve atrophy (25%) **Sensorineural hearing loss (10%) **Diabetes mellitus (10%) or glucose intolerance (20%) Natural history *Ataxia usually develops in childhood or early teens *Rate of progression is variable **Mean age of loss of ambulation is 25 years **Death usually occurs in 30's ***Cardiomyopathy ***Diabetes ***Pneumonia due to dysphagia *25% of patients have atypical findings **Late-onset FRDA (LOFA) ***Approximately 15% of patients with FRDA ***Age of onset greater than 25 years of age ***Usually have repeat size smaller than 500 **FRDA with retained reflexes (FARR) ***12% of patients with FRDA ***Show brisk tendon reflexes for up to 10 years after disease onset **FRDA with slowly progressive disease ***Disease progression slower in Acadian patients ***Age on onset and neurological manifestations similar Testing *Molecular genetic testing can be used to identify mutations in X25/FRDA **Shortest repeat length causing disease has not yet been determined for sure **<1% of patients who satisfy clinical diagnostic criteria have no identifiable mutation *Carrier testing **Can be offered if two disease-causing mutations are identified in proband **Alleles in premutation range may be transmitted unchanged or may expand *Prenatal testing **Clinically available for couples at 25% risk for having child with FRDA1 if both disease causing mutations are known **DNA from amniocentesis at 16-18 weeks or CVS at 10-12 weeks can be analyzed Management *No therapy is known to stop, delay, or reverse disease progression *Future therapies may include: **Drug therapy **Gene therapy **Other pathophysiology-based treatments *Support **Psychological support **Prostheses, walking aids, and wheelchairs may help patients maintain an active lifestyle **Physical therapy **Speech therapy **Orthopedic intervention for scoliosis and foot deformities **Treatment of cardiac disease and diabetes Differential Diagnosis *Demyelinating form of hereditary motor and sensory neuropathy type I (HMSNI or CMT1) **Childhood symptoms may be similar **Nerve conduction studies or DNA testing can determine definitively *Vitamin E deficiency **Should be considered in cases that don't show a GAA expansion **Fulfill diagnostic criteria for FRDA but often have titubation and hyperkinesia **Treated with Vitamin E supplements *Other early onset ataxias present with different clinical findings Psychosocial Issues *Feelings of guilt, anxiety *Pregnancy issues: preimplantation genetic diagnosis, prenatal testing, possible pregnancy termination *Discussion with other family members about risk, inheritance *Disruption of work, school, social life for those affected Resources *National Ataxia Foundation :Phone: 763-553-0020 :Email: naf@ataxia.org *Muscular Dystrophy Association :Phone: 520-529-5300 or 8-572-1717 :Email: mda@mdausa.org :Web: www.mdausa.org *International Network of Ataxia Friends (INTERNAF) :Web: internaf.org Resources Geneclinics. "Friedreich Ataxia" Web: www.geneclinics.org Online Mendelian Inheritance in Man. "Friedreich Ataxia" Web: www.ncbi.nlm.nih.gov Notes The information in this outline was last updated in 2001. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.